Role of glucocorticoids on the synaptic trace of memory

The complexity of the classical inverted U-shaped relationship between cortisol levels and responses transposable to stress reactivity has led to an incomplete understanding of the mechanisms enabling healthy and toxic effects of stress on brain and behavior. A clearer, more detailed, picture of those relationships can be obtained by integrating cortisol effects on large-scale brain networks, in particular, by focusing on neural network configurations from the perspective of inhibition and excitation. A unifying view of Semon and Hebb’s theories of cellular memory links the biophysical and metabolic changes in neuronal ensembles to the strengthening of collective synapses. In that sense, the neuronal capacity to record, store and retrieve information directly relates to the adaptive capacity of its connectivity and metabolic reserves. Here, we use task-activated cell ensembles or simply engram cells as an example to demonstrate that the adaptive behavioral responses to stress result from collective synapse strength within and across networks of interneurons and excitatory ones.

Soluble and solid amyloid pathways reveal differential dynamics of glutamatergic synapses that depend on neurocentric cortisol receptor signaling

Excessive glucocorticoid exposure during chronic stress causes synapse loss and learning impairment. Under normal physiological conditions, glucocorticoid activity oscillates in synchrony with the circadian rhythm. Whether and how endogenous glucocorticoid oscillations modulate synaptic plasticity and learning is unknown. Here we show that circadian glucocorticoid peaks promote postsynaptic dendritic spine formation in the mouse cortex after motor skill learning, whereas troughs are required for stabilizing newly formed spines that are important for long-term memory retention. Conversely, chronic and excessive exposure to glucocorticoids eliminates learning-associated new spines and disrupts previously acquired memories. Furthermore, we show that glucocorticoids promote rapid spine formation through a non-transcriptional mechanism by means of the LIM kinase-cofilin pathway and increase spine elimination through transcriptional mechanisms involving mineralocorticoid receptor activation. Together, these findings indicate that tightly regulated circadian glucocorticoid oscillations are important for learning-dependent synaptic formation and maintenance. They also delineate a new signaling mechanism underlying these effects.

If the engram of long-term memory is encoded by structural changes of neuronal circuits, they are expected to be present at distant time points after learning, to be specific of circuits activated by learning, and sensitive to behavioral contingencies. In this review we present new concepts that emerged from in vivo imaging studies that tracked the structural bases of the memory trace. A fine balance of spine formation and spine elimination needed for behavioral adaptation to new experience is regulated by glucocorticoids, which are secreted in synchrony with circadian rhythms and in response to stress. Disruption of glucocorticoid oscillations frequently observed in psychiatric disorders like depression and post-traumatic stress produces spine turnover defects and learning disabilities. These new findings provide a new framework for explaining the potent but complex mnemonic effects of glucocorticoids. © 2015 médecine/sciences – Inserm.

Stress can either promote or impair learning and memory. Such opposing effects depend on whether synapses persist or decay after learning. Maintenance of new synapses formed at the time of learning upon neuronal network activation depends on the stress hormone activated glucocorticoid receptor (GR) and neurotrophic factor release. Whether and how concurrent GR and neurotrophin signaling integrate to modulate synaptic plasticity and learning is unknown. Here we show that deletion of the neurotrophin BDNF-dependent GR phosphorylation sites (GR-PO 4 ) impairs long-term memory retention and maintenance of newly formed postsynaptic dendritic spines in the mouse cortex after motor skills training. Chronic stress and the BDNF polymorphism Val66Met disrupt the BDNF-dependent GR-PO 4 pathway necessary for preserving training-induced spines and previously acquired memories. Conversely, enrichment living promotes spine formation but fails to salvage training-related spines in mice lacking BDNF-dependent GR-PO 4 sites, suggesting it is essential for spine consolidation and memory retention. Mechanistically, spine maturation and persistence in the motor cortex depend on synaptic mobilization of the glutamate receptor GluA1 mediated by GR-PO 4 . Together, these findings indicate that regulation of GR-PO 4 via activity-dependent BDNF signaling is important for learning-dependent synapses formation and maintenance. They also define a new signaling mechanism underlying these effects. SIGNIFICANCE STATEMENT Signal transduction of receptors tyrosine kinase and nuclear receptors is essential for homeostasis. Phosphorylation is one of the currencies used by these receptors to support homeostatic reactions in learning and memory. Here we show that consolidation of learning-induced neuroplasticity is made possible via stress activated glucocorticoid nuclear receptor phosphorylation through the brain-derived neurotrophic tyrosine kinase pathway. Crosstalk between these pathways is specific of cell types and behavioral experience ( e.g . learning, stress and enrichment living). Disruption of this response may contribute to the pathophysiology of stress-related disorders and treatment resistance.

Significance Signal transduction upon activation of receptor tyrosine kinases by neurotrophins and nuclear receptors by glucocorticoids is essential for homeostasis. Phosphorylation (PO 4 ) is one way these receptors communicate with one another to support homeostatic reactions in learning and memory. Using a newly developed glucocorticoid receptor (GR)-PO 4 –deficient knock-in mouse, we show that consolidation of learning-induced neuroplasticity depends on both GR-PO 4 and neurotrophic signaling. Cross-talk between these pathways affects experience-dependent neuroplasticity and behavior, extending previous implications of neurotrophic priming of glucocorticoid response for adaptive plasticity to chronic stress and antidepressant response. Therefore, a disruption of cross-talk between these pathways by, for example, the misalignment of circadian glucocorticoid release and experience-dependent neurotrophic signaling may contribute to the pathophysiology of stress-related disorders.